tbuckley/cabot-search huggingface dataset:
Abstract 1705: <i>SPOP</i>: An essential gene for normal and prostate tumor cells
Authors: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer (PC) is the single most common and second-most lethal cancer in men, with over 268,000 estimated cases and over 34,500 estimated deaths in the US in 2022. The Speckle-Type POZ protein (SPOP) mutant subclass of PC accounts for 10% to 15% of all primary PC cases. SPOP is an adaptor for Cullin3/Ring (CUL3-RING)-type E3 ubiquitin ligase complexes and provides substrate specificity. The Cancer Genome Atlas (TCGA) studies show that SPOP is the most frequently mutated gene in primary prostate cancer (PC). Interestingly, PC-associated SPOP mutations are always missense and occur in a heterozygous fashion. The current gap in knowledge is the lack of understanding of the role of wildtype SPOP in PC. Methods: By utilizing prostate specific SPOP knockout (KO) mice, we recently reported increased levels of AR and MYC protein and increased cellular turnover (both proliferation and apoptosis) in the prostate luminal epithelium compared to wildtype prostates. We now characterized these mice for the expression of Cre protein and SPOP mRNA at different age using immunohistochemistry and RNA in situ hybridization. Furthermore, we performed RNA-sequencing analysis in the SPOP knockout mice and matched control littermates. Moreover, we performed RNA-seq in LNCaP, LNCaP-Abl, and RWPE1 cells following SPOP inhibition via siRNA targeting SPOP. Finally, we compared our SPOP inhibition signature from in vitro cell lines and prostate specific SPOP knockout murine model to gain insights about the role of wildtype SPOP protein in the prostate epithelium. Result: Using our Spopfl/fl;PBCre+ model, we observed SPOP floxed cells are rapidly lost and the murine prostate epithelium was repopulated with SPOP wildtype carrying cells. Similarly, knockdown (KD) of SPOP through siRNA treatment in a panel of PC cell lines resulted in a significant reduction in cell viability. These observations suggest that SPOP is important for the normal prostate cell viability. Further transcriptomic profiling of SPOP KO (from transgenic murine model) as well as siSPOP treated in vitro prostate cell lines revealed a significant reduction in the transcriptional activity of the AR. Conclusion: Our data illustrate for the first time a critical role for SPOP in the growth and survival of the prostate epithelium and prostate cancer cell. Our findings further validates SPOP as a important therapeutic target for the treatment of prostate cancer. Citation Format: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar. SPOP: An essential gene for normal and prostate tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1705.
Abstract 4202: Kidney function and risk of renal cell carcinoma
Authors: Karine Alcala, Nicolas Alcala, Richard Martin, Paul Brennan, David Muller, Hilary A. Robbins, Mattias Johansson
Journal: Cancer Research (2023)

Abstract Background: The relationship between kidney function and risk of renal cell carcinoma (RCC) is not well understood. In this study, we evaluated the association between estimated glomerular filtration rate (eGFR) and risk of incident RCC, and assessed whether this association depends on time between eGFR measurement and RCC diagnosis. We also sought to evaluate if eGFR may be useful to predict RCC risk. Methods: We conducted this study in the UK Biobank cohort based on 440,983 participants of whom 984 were diagnosed with RCC during 4,552,747 person-years of follow-up. The temporal relation between kidney function and RCC was evaluated with flexible parametric survival models for eGFR calculated from creatinine, cystatin C and both, adjusted for C-reactive protein (CRP) and common RCC risk factors. We also assessed the benefit of combining CRP and eGFR with a published RCC risk prediction model by estimating calibration and discrimination using a resampling algorithm as internal validation. Results: We found that a lower eGFR - an indication of poor kidney function - was associated with higher RCC risk when measured up to five years prior to diagnosis. We estimated the RCC hazard ratio per standard deviation decrease in eGFR when measured one year before diagnosis at 1.22 (95% confidence interval [95% CI]: 1.11-1.34), and at 1.14 (95% CI: 1.05-1.19) when measured five years before diagnosis. The corresponding RCC HR for eGFR measured ten years before diagnosis was 1.03 (95% CI: 0.95-1.12). Adding eGFR to the RCC risk model provided a small improvement in risk discrimination 2 years before diagnosis with a C-index of 0.76 (95% CI: 0.71-0.81) compared to the published model (0.73, 95% CI: 0.68-0.79). Conclusion: This study demonstrated that markers of kidney function are robustly associated with RCC risk when measured within the last five years leading up to diagnosis. However, kidney function markers do not seem to provide important improvements in RCC risk discrimination beyond established risk factors. Citation Format: Karine Alcala, Nicolas Alcala, Richard Martin, Paul Brennan, David Muller, Hilary A. Robbins, Mattias Johansson. Kidney function and risk of renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4202.
Abstract 4960: Fascin inhibitor decreases gynecological cancer cell growth through cell cycle regulation
Authors: Wanyi Chen, Yufeng Wang, Liangliang Ji, Ming O. Li, Xin-Yun Huang
Journal: Cancer Research (2023)

Abstract The actin cytoskeleton is essential for maintaining cell morphology and architecture. Actin-bundling proteins such as fascin cross-link actin filaments into bundles and play critical roles in regulating cell protrusion and motility. Fascin protein expression is low or absent in normal human epithelial cells but high in cancer cells. Elevated fascin levels are correlated with aggressive clinical progression, poor prognosis, and shorter survival outcomes. It is regarded as a cancer progression biomarker and a therapeutic target. We have developed a small molecule fascin inhibitor and shown its efficacy in blocking tumor cell migration, invasion, and metastasis, as well as prolonging the overall survival of mice bearing different types of cancers. Our recent data reveals a new mechanism of this fascin inhibitor in cell cycle regulation of gynecological cancer cells. It blocks the G2/M progression and decreases the mitotic index. Fascin inhibitor treatment also results in aneuploidy, which is a well-known factor for triggering downstream apoptosis. Our data suggests that fascin is involved in maintaining the fidelity of chromosome segregation and cell division. This will advance our understanding of the interplay between actin and microtubule cytoskeleton during cell mitosis. Citation Format: Wanyi Chen, Yufeng Wang, Liangliang Ji, Ming O. Li, Xin-Yun Huang. Fascin inhibitor decreases gynecological cancer cell growth through cell cycle regulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4960.
Abstract 2473: Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma
Authors: Makoto Miyazaki, Yuko Nagamura, Hideki Yamaguchi
Journal: Cancer Research (2023)

Abstract Diffuse-type gastric carcinoma is characterized by highly invasive growth, massive fibrosis, and peritoneal metastasis. Peritoneal metastasis is the leading cause of death in diffuse-type gastric carcinoma; however, the underlying molecular mechanisms remain largely unknown. Recent studies have established a concept of polyclonal metastasis, in which metastases arise from circulating tumor cell clusters with high metastatic potential. Polyclonal metastasis is a cause of tumor heterogeneity that contributes to tumor progression and therapeutic resistance. However, the clonality of peritoneally metastasized tumors and the evidence for polyclonal metastasis in diffuse-type gastric carcinoma have been poorly elucidated. In this study, we utilized multicolor fluorescent lineage tracking to examine the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor exhibited multicolor fluorescence, showing that it contains multiclonal cancer cell populations. Peritoneal cytology and in situ fluorescent imaging of micrometastases revealed that multicolored cancer cell clusters formed within the peritoneal cavity and collectively attached to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients elicited cancer cell clustering, which was inhibited by anticoagulants. Immunofluorescence and immunoblotting revealed that cancer cell clusters formed in vitro and in vivo were associated with fibrin formation. Moreover, tissue factor knockout in cancer cells significantly reduced fibrin formation, cell clustering, peritoneal attachment, and peritoneal metastasis. In an in vitro adhesion assay, fibrin formation facilitated the cancer cell-mesothelial cell adhesion. Thus, these results demonstrate that cancer cells activate the coagulation cascade through tissue factor to form fibrin-mediated cell clusters and accelerate peritoneal attachment, leading to the development of polyclonal peritoneal metastasis. Our findings identify a novel mechanism of peritoneal metastasis that may be a potential therapeutic target. Citation Format: Makoto Miyazaki, Yuko Nagamura, Hideki Yamaguchi. Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2473.
Abstract 1427: NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase
Authors: Eun-Taex Oh, Ha Gyeong Kim, Yunmi Cho, Heon Joo Park
Journal: Cancer Research (2023)

Abstract Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with tumor cell proliferation and growth in several human cancer types. However, the molecular mechanisms underlying the activity of NQO1 in cell cycle progression are currently unclear. Here, we report a novel function of NQO1 in modulation of cyclin-dependent kinase subunit (CKS1), a cell cycle regulator, at the G2/M phase, through effects on the stability of c-Fos. We analyzed the roles of NQO1/c-Fos/CKS signaling pathway in cell cycle progression in cancer cells using synchronization of cell cycle and flow cytometry. The mechanisms of NQO1/c-Fos/CKS1-mediated regulation of cell cycle progression in cancer cells were studied by siRNA, overexpression system, reporter assay, co-immunoprecipitation, pull-down assay, microarray analysis, and CDK1 kinase assay. In addition, publicly available data sets and immunohistochemistry were used to investigate the correlation between NQO1 expression levels and clinicopathological features in cancer patients. Our results suggest that NQO1 directly interacts with the unstructured DNA-binding domain of c-Fos implicated in proliferation, differentiation, development and survival of cancer and inhibits its proteasome-mediated degradation, thereby inducing CKS1 expression and regulating cell cycle progression at the G2/M phase. Notably, NQO1 deficiency in human cancer cell lines led to suppression of c-Fos-mediated CKS1 expression and cell cycle progression. Consistent with this finding, high NQO1 expression was correlated with increased CKS1 and poor prognosis in cancer patients. Our collective results support a novel regulatory role of NQO1 in the mechanism of cell cycle progression at the G2/M phase through effects on c-Fos/CKS1 signaling pathway in cancer. Citation Format: Eun-Taex Oh, Ha Gyeong Kim, Yunmi Cho, Heon Joo Park. NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1427.
Abstract 2452: A study of AXIN2-regulatory mechanisms and their role in the stem cell origin of human CRC
Authors: Chi Zhang, Caroline Facey, Lynn Opdenaker, Bruce Boman
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) originates from stem cell (SC) overpopulation, which is driven by constitutively activated WNT-signaling due to mutations in genes that encode components of the WNT-signaling pathway, particularly APC. WNT-signaling is regulated by the ꞵ-catenin destruction complex, which contains APC, AXIN1, AXIN2 and other proteins. Availability of AXIN1/2 proteins is the rate-limiting factor of destruction complex function. The Gap in Our Knowledge is how to target AXIN in order to restore destruction complex function in APC-mutant colon tissues. A growing body of scientific evidence shows both AXIN1 &amp; AXIN2 promote ꞵ-catenin degradation and AXINs are hub proteins involved in regulation of multiple cellular pathways that play a role in tumor phenotype. While AXIN2 expression is up-regulated in CRC, the increased level of AXIN2 is incapable of deterring CRC progression. This evidence indicates that AXIN2 is in a key pivotal position to therapeutically target WNT signaling whereby the availability of AXIN2 can be used to fine-tune ꞵ-catenin levels. We HYPOTHESIZE that the intracellular level of AXIN2 and AXIN1 determines the degree of WNT-signaling activity in APC-mutant CRC cells and affects tumor cell phenotypic properties relevant to CRC progression. Accordingly, we have created siRNA-mediated AXIN2 knockdown and lentiviral-based AXIN2 overexpressing HT29 and SW480 cells to study the effect of modulating AXIN2 levels. The RESULTS show that decreasing AXIN2 leads to increased WNT-signaling and increasing AXIN2 leads to increased expression of WNT-target genes. Moreover, increasing AXIN2 leads to diminished tumor cell phenotype as shown by: 1) lower cell proliferation rate; 2) up-regulated expression of SC markers (ALDH &amp; LGR5) and increased SC population size (ALDEFLUOR+ or LGR5+); 3) down-regulated cell cycle rate; 4) down-regulated apoptosis. Moreover, our bioinformatics analyses of the effect of tankyrase inhibitors (TIs), which prevent AXIN degradation, indicate that efficacy of TIs against CRC cells depends on the APC genotype. Thus, our findings indicate that AXIN2, by down-regulating WNT-signaling, reduces cancer stem cell phenotype including decreased SC population size. SIGNIFICANCE: discovering ways to target AXIN2-based mechanisms has vast clinical importance for developing new treatment against CRC. Citation Format: Chi Zhang, Caroline Facey, Lynn Opdenaker, Bruce Boman. A study of AXIN2-regulatory mechanisms and their role in the stem cell origin of human CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2452.
Abstract 5792: The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models
Authors: Amani Yehya, Alissar Monzer, Kevork Wakimian, Fatima Ghamlouche, Nour Saheb, Ayman Tawil, Hala Gali-Muhtasib, Deborah Mukherji, Albert El-Hajj, Wassim G. Abou-Kheir
Journal: Cancer Research (2023)

Abstract Aim: To investigate the anticancer potential of the novel quinone DIQ on prostate cancer (PCa) cells in two-dimensional (2D) and three-dimensional (3D) in vitro. Methods: The anti-proliferative effect of DIQ on PC3 and DU145 PCa cell lines was determined in vitro by using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays. In addition, the potency of DIQ was tested on the formation and size of PCa cell-derived prostatospheres and organoids grown in a specialized 3D-culture system. Also, 3D organoids were established from fresh tissue samples representing different stages of PCa obtained from consented patients who underwent radical prostatectomy at the American University of Beirut Medical Center (AUBMC) according to appropriate Institutional Review Board (IRB) approval guidelines. This model was used to assess DIQ individualized tumor response on organoids growth and the effect was evaluated by quantifying the number of organoids formed (OFC) and calculating the average size (diameters). Results: Our results showed that DIQ significantly attenuated cell proliferation and viability in PC3 and DU145 PCa cell lines. DIQ also reduced the formation ability and size of PC3 and DU145 prostatospheres and organoids at sub-toxic doses of 1 µM. Potently, DIQ displayed a significant decrease in both the count and the size of the different patient-derived organoids as compared to their respective control. Conclusion: This study provides promising clues for the use of the novel anticancer therapeutic DIQ in targeting CSCs, findings that may have promising therapeutic implications for PCa patients. Citation Format: Amani Yehya, Alissar Monzer, Kevork Wakimian, Fatima Ghamlouche, Nour Saheb, Ayman Tawil, Hala Gali-Muhtasib, Deborah Mukherji, Albert El-Hajj, Wassim G. Abou-Kheir. The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5792.
Abstract 163: Establishment of pancreatic ductal adenocarcinoma organoids model using endoscopic ultrasonography-guided fine needle biopsy: a new window into understanding pancreatic ductal adenocarcinoma tumor biology
Authors: Hyemin Kim, Hongui Cha, Se-Hoon Lee, Joo Kyung Park
Journal: Cancer Research (2023)

Abstract Background &amp; Aims: Tumor biology studies of pancreatic ductal adenocarcinoma (PDAC) used surgical specimens, even though most PDACs are unresectable. The aims of the study were to 1) establish PDAC organoids platform from endoscopic ultrasonography (EUS)-guided fine needle biopsy (FNB), 2) investigate clinicopathologic and genomic characterization, and 3) find out the clinical applicability of the patient-derived PDAC organoids model from PDAC diagnosis to treatment timeline. Methods: The patients with suspected PDACs were enrolled prospectively, and PDAC minimal specimens were acquired from EUS-guided FNB at Samsung Medical Center from 2015 to 2019. Results: Ninety-four PDAC organoids were successfully established (94/113, 83.2%) via EUS-guided FNB within 8.2±2.6 days. Clinical factors were also analyzed associated with the success rate in establishing PDAC organoids; specimens with high cellularity (&amp;gt;10 clusters) were an independent factor in multivariate analysis. Whole exome sequencing showed the high concordance between primary PDAC and its organoid and more enriched genetic alterations in organoids. In addition, the high-throughput screening (HTS) drug test revealed that the clinical correlation with real-world data was 12 out of 15 between PDAC organoids and the chemotherapeutic response of the study patients. Whole-transcriptome sequencing identified genes and pathways associated with the drug responses. Conclusions: We have achieved the PDAC organoid platform in a high success rate via EUS-guided FNB, and the concordance between primary PDAC and its organoid seems very high. More importantly, the HTS drug test showed that PDAC organoids may well reflect clinical chemotherapeutic response and may also be used as the “Patient Avatar Model” in clinical practice on time. Citation Format: Hyemin Kim, Hongui Cha, Se-Hoon Lee, Joo Kyung Park. Establishment of pancreatic ductal adenocarcinoma organoids model using endoscopic ultrasonography-guided fine needle biopsy: a new window into understanding pancreatic ductal adenocarcinoma tumor biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 163.
Abstract 2461: The cell migration inhibitor dihydromotuporamine C regulates actin-myosin contractility and actin polymerization
Authors: Laurence von Kalm, Corey Seavey
Journal: Cancer Research (2023)

Abstract The motuporamines are a promising class of anti-metastatic compounds. Dihydromotuporamine C (Motu33) has been shown to activate the small GTPase RhoA, however, little is known about subsequent downstream events leading to cell migration inhibition. In the present study, we investigated the mechanism of action of Motu33 and a synthetic derivative, Motu-(CH2)-33, in Drosophila by manipulating the gene dose of positive and negative regulators of actin dynamics. Consistent with previous findings, reduced gene dose of Rho1 (the Drosophila RhoA ortholog) attenuates motuporamine activity, confirming that RhoA/Rho1 is targeted by these compounds. Actin-myosin contraction is controlled by the RhoA-ROCK-myosin regulatory light chain (MRLC) pathway. Reduced gene dose of the myosin binding subunit of myosin phosphatase, a negative regulator of the RhoA-ROCK-MRLC pathway, enhances motuporamine activity indicating that the motuporamines stimulate actin-myosin contraction through activation of the myosin regulatory light chain. RhoA also activates diaphanous (dia) to control actin polymerization. Surprisingly, reduced gene dose of dia enhances motuporamine activity, suggesting that the motuporamines act on dia in a RhoA-independent manner. Reduction in gene dose of the Drosophila Rac orthologs also enhances motuporamine activity. In contrast, motuporamine activity is unaltered by reduced gene dose of slingshot (ssh) which acts to trigger actin severing and depolymerization. Since ssh is directly regulated by Rac, the enhanced activity of motuporamines observed when Rac gene dose is reduced may reflect an indirect mode of action on the Rac GTPases leading to increased RhoA activity. In summary, these findings demonstrate that motuporamines act through RhoA and diaphanous to regulate actin-myosin contractility and actin polymerization. Citation Format: Laurence von Kalm, Corey Seavey. The cell migration inhibitor dihydromotuporamine C regulates actin-myosin contractility and actin polymerization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2461.